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Haruto Hayashi,1 Takehide Nogita,2,3 Hideki Maeda1,2 1Department of Regulatory Science, Faculty of Pharmacy, Meiji Pharmaceutical University, Tokyo, Japan; 2Department of Regulatory Science, Graduate School of Pharmaceutical Science, Meiji Pharmaceutical University, Tokyo, Japan; 3CMIC Co Ltd., Tokyo, JapanCorrespondence: Hideki Maeda, Department of Regulatory Science, Faculty of Pharmacy, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose-city, Tokyo, 204-5255, Japan, Tel/Fax +81-42-495-8952, Email maeda@my-pharm.ac.jpPurpose: An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them.Patients and Methods: We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional).Results: All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was “requests from physicians and medical institutions” (nine companies, 90.0%), and the most common reason for not implementing an EACT was “the applicability of the system” (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised.Conclusion: An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due.Keywords: clinical trials, investigational new drugs, patient access, semi-structured interview

Motoko Tachihara,1 Kayoko Tsujino,2 Takeaki Ishihara,3 Hidetoshi Hayashi,4 Yuki Sato,5 Takayasu Kurata,6 Shunichi Sugawara,7 Isamu Okamoto,8 Shunsuke Teraoka,9 Koichi Azuma,10 Haruko Daga,11 Masafumi Yamaguchi,12 Takeshi Kodaira,13 Miyako Satouchi,14 Mototsugu Shimokawa,15 Nobuyuki Yamamoto,9 Kazuhiko Nakagawa4 On behalf of members of the West Japan Oncology Group (WJOG)1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe City, Japan; 2Department of Radiation Oncology, Hyogo Cancer Center, Akashi City, Japan; 3Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe City, Japan; 4Department of Medical Oncology, Kindai University, Osakasayama City, Japan; 5Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe City, Japan; 6Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata City, Japan; 7Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai City, Japan; 8Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan; 9Internal Medicine III, Wakayama Medical University, Wakayama, Japan; 10Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka City, Japan; 11Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan; 12Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan; 13Departments of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya City, Aichi, Japan; 14Department of Thoracic Oncology, Hyogo Cancer Center, Akashi City, Japan; 15Department of Biostatistics, Yamaguchi University Graduate School of Medicine Yamaguchi, Ube City, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpAbstract: Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.Keywords: clinical study, locally advanced non-small cell lung cancer, immunotherapy, programmed cell death ligand-1, durvalumab, radiation

Keitaro Shimozaki,1 Yasutaka Sukawa,1 Noriko Beppu,2 Isao Kurihara,3 Shigeaki Suzuki,4 Ryuichi Mizuno,5 Takeru Funakoshi,6 Shinnosuke Ikemura,7,8 Kai Tsugaru,1 Kazuhiro Togasaki,1 Kenta Kawasaki,1 Kenro Hirata,1 Hideyuki Hayashi,8 Yasuo Hamamoto,8 Hiromasa Takaishi,8 Takanori Kanai1 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 2Department of Pharmacy, Keio University Hospital, Tokyo, Japan; 3Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 4Department of Neurology, Keio University School of Medicine, Tokyo, Japan; 5Department of Urology, Keio University School of Medicine, Tokyo, Japan; 6Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; 7Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 8Keio Cancer Center, Keio University School of Medicine, Tokyo, JapanCorrespondence: Yasutaka Sukawa Tel +81-3-3353-1211Fax +81-3-5363-6247Email sukawa@keio.jpPurpose: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice.Patients and Methods: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model.Results: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33– 0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346– 0.647; P < 0.0001).Conclusion: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.Keywords: immune checkpoint inhibitors, programmed cell death 1, prognosis

Hiroshi Matsuda,1 Kota Yokoyama,2 Noriko Sato,2 Kengo Ito,3 Kiyotaka Nemoto,4 Hiroshi Oba,5 Haruo Hanyu,6 Hidekazu Kanetaka,6 Sunao Mizumura,7 Shin Kitamura,8 Hitoshi Shinotoh,9 Hitoshi Shimada,9 Tetsuya Suhara,9 Hitoshi Terada,10 Tomoya Nakatsuka,10 Shinobu Kawakatsu,11 Hiroshi Hayashi,12 Takashi Asada,13 Tetsutaro Ono,14 Tomoaki Goto,14 Keiko Shigemori14 1Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 2Department of Radiology, National Center Hospital of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 3Innovation Center for Clinical Research, National Center for Geriatrics and Gerontology, Obu, Japan; 4Department of Psychiatry, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan; 5Department of Radiology, Teikyo University Hospital, Itabashi-ku, Tokyo, Japan; 6Department of Geriatric Medicine, Tokyo Medical University Hospital, Shinjuku-ku, Tokyo, Japan; 7Department of Radiology, Toho University Omori Medical Center, Oota-ku, Tokyo, Japan; 8Department of Internal Medicine, Nippon Medical School Musashi Kosugi Hospital, Kawasaki, Japan; 9Department of Functional Brain Imaging Research, Clinical Research Cluster, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; 10Department of Radiology, Toho University Sakura Medical Center, Sakura, Japan; 11Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan; 12Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan; 13Section of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo, Japan; 142nd Group, 2nd Planning Department, 1st Integrated Communication Division, Communication and Information Center, Information Innovation Operations, Dai Nippon Printing Co., Ltd., Tokyo, JapanCorrespondence: Hiroshi MatsudaIntegrative Brain Imaging Center, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, JapanTel +81 42 341 2711Email matsudah@ncnp.go.jpBackground: The differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) is particularly important because DLB patients respond better to cholinesterase inhibitors but sometimes exhibit sensitivity to neuroleptics, which may cause worsening of clinical status. Antemortem voxel-based morphometry (VBM) using structural MRI has previously revealed that patients with DLB have normal hippocampal volume, but atrophy in the dorsal mesopontine area.Objectives: The aim of this multicenter study was to determine whether VBM of the brain stem in addition to that of medial temporal lobe structures improves the differential diagnosis of AD and DLB.Methods: We retrospectively chose 624 patients who were clinically diagnosed with either DLB (239 patients) or AD (385 patients) from 10 institutes using different MR scanners with different magnetic field strengths. In all cases, VBM was performed on 3D T1-weighted images. The degree of local atrophy was calculated using Z-score by comparison with a database of normal volumes of interest (VOIs) in medial temporal lobe (MTL) and the dorsal brain stem (DBS). The discrimination of DLB and AD was evaluated using Z-score values in these two VOIs. MRI data from 414 patients were used as the training data set to determine the classification criteria, with the MRI data from the remaining 210 patients used as the test data set.Results: The DLB and AD patients did not differ with respect to mean age or Mini-Mental State Examination scores. Z-index scores showed that there was significantly more atrophy in MTL of AD patients, compared to DLB patients and in DBS of DLB patients, compared to AD patients. The discrimination accuracies of VBM were 63.3% in the test data set and 73.4% in the training data set.Conclusion: VBM of DBS in addition to that of MTL improves the differentiation of DLB and AD.Keywords: dementia with Lewy bodies, Alzheimer’s disease, MRI, voxel-based morphometry

Iwao Nakamura, Eiji Ichimura, Rika Goda, Hitomi Hayashi, Hiroko Mashiba, Daichi Nagai, Hirofumi Yokoyama, Takeshi Onda, Akira Masuda Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan Abstract: In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX (Cmax_PTX and AUC0-inf._PTX) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®–NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX–albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275). Keywords: micelle, paclitaxel, peripheral neurotoxicity, dorsal root ganglion, vascular permeability

Yoshikatsu Hosoda, Shoji Kuriyama, Yoko Jingami, Hidetsugu Hattori, Hisako Hayashi, Miho Matsumoto Department of Ophthalmology, Otsu Red-Cross Hospital, Otsu, Japan Purpose: The purpose of this study was to compare the level of patient pain during the phacoemulsification and implantation of foldable intraocular lenses while under topical, intracameral, or sub-Tenon lidocaine.Patients and methods: This was a retrospective study. Three hundred and one eyes subjected to cataract surgery were included in this study. All eyes underwent phacoemulsification surgery and intraocular lens implantation using topical, sub-Tenon, or intracameral anesthesia. The topical group received 4% lidocaine drops, and the intracameral group received a 0.1–0.2 cc infusion of 1% preservative-free lidocaine into the anterior chamber through the side port combined with topical drops of lidocaine. The sub-Tenon group received 2% lidocaine. Best-corrected visual acuity, corneal endothelial cell loss, and intraoperative pain level were evaluated. Pain level was assessed on a visual analog scale (range 0–2).Results: There were no significant differences in visual outcome and corneal endothelial cell loss between the three groups. The mean pain score in the sub-Tenon group was significantly lower than that in the topical and intracameral groups (P=0.0009 and P=0.0055, respectively). In 250 eyes without high myopia (

Yoshiaki Kubota,1 Kuniya Asai,1 Koji Murai,1 Yayoi Tetsuou Tsukada,1 Hiroki Hayashi,2 Yoshinobu Saito,2 Arata Azuma,2 Akihiko Gemma,2 Wataru Shimizu1 1Department of Cardiovascular Medicine, 2Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Background: COPD is concomitantly present in ~30% of patients with heart failure. Here, we investigated the pulmonary function test parameters for left ventricular (LV) diastolic dysfunction and the relationship between pulmonary function and LV diastolic function in patients with COPD. Patients and methods: Overall, 822 patients who underwent a pulmonary function test and echocardiography simultaneously between January 2011 and December 2012 were evaluated. Finally, 115 patients with COPD and 115 age- and sex-matched control patients with an LV ejection fraction of ≥50% were enrolled. Results: The mean age of the patients was 74.4±10.4 years, and 72.3% were men. No significant differences were found between the two groups regarding comorbidities, such as hypertension, diabetes mellitus, and anemia. The index of LV diastolic function (E/e') and the proportion of patients with high E/e' (defined as E/e' ≥15) were significantly higher in patients with COPD than in control patients (10.5% vs 9.1%, P=0.009; 11.3% vs 4.3%, P=0.046). E/e' was significantly correlated with the residual volume/total lung capacity ratio. Univariate and multivariate analyses revealed severe COPD (Global Initiative for Chronic Obstructive Lung Disease III or IV) to be a significant predictive factor for high E/e' (odds ratio [OR] 5.81, 95% confidence interval [CI] 2.13–15.89, P=0.001 and OR 6.00, 95% CI 2.08–17.35, P=0.001, respectively). Conclusion: Our data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation. Keywords: COPD, heart failure, left ventricular diastolic dysfunction

Ken Nishihara,1 Hisashi Kawai,2 Hiroyuki Hayashi,3 Hideo Naruse,4 Akihito Kimura,4 Toshiaki Gomi,5 Fumihiko Hoshi1 1Department of Physical Therapy, Saitama Prefectural University, Saitama, Japan; 2Health Promotion Management Office, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan; 3Center for University-wide Education, Saitama Prefectural University, Saitama, Japan; 4Faculty of Health Sciences, Tokyo Ariake University of Medical and Health Sciences, Tokyo, Japan, 5Faculty of Nursing, Tokyo Ariake University of Medical and Health Sciences, Tokyo, Japan Background: The skeletal muscle echo intensity (EI) during ultrasound imaging has been investigated to evaluate the muscle quality. However, EI fluctuates according to the scanning conditions.Methods: The motor functions and ultrasound images of 19 elderly (73±3.2 years) and 19 young (22±1.5 years) individuals were investigated and an EI frequency component was assessed for more reliable evaluations. Healthy elderly and young subjects participated in this study. The motor functions were assessed during walking and according to the knee extension muscle strength. The muscle thicknesses of rectus femoris (RF), vastus intermedius (VI), and quadriceps femoris (QF) were investigated. EIs were calculated and the mean frequencies of the regions of interest (MFROIs) for RF and VI were analyzed. Results: EIs and MFROIs were greater in elderly subjects than in young subjects (P

Tomohiro Mizuno,1,2 Takahiro Hayashi,3 Sayo Hikosaka,1 Yuka Shimabukuro,1 Maho Murase,1 Kazuo Takahashi,2 Hiroki Hayashi,2 Yukio Yuzawa,2 Tadashi Nagamatsu,1 Shigeki Yamada3 1Department of Analytical Pharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan; 2Department of Nephrology, School of Medicine, Fujita Health University, Toyoake, Japan; 3Department of Clinical Pharmacy, School of Medicine, Fujita Health University, Toyoake, Japan Background: Maintenance of low serum urate levels is important for the management of gout. Achieving the recommended serum urate levels of less than 6.0 mg/dL is difficult in elderly (65 years of age or older) patients with renal impairment. Xanthine oxidase inhibitors allopurinol and febuxostat are used for this purpose. Although febuxostat had been shown to be efficacious in elderly patients, its safety and efficacy in elderly female patients with hyper­uricemia remain unclear.Objective: The aim of this study was to assess the efficacy and safety of febuxostat in elderly female patients.Methods: We studied a retrospective cohort study. The study included elderly Japanese patients (65 years of age or older) who were treated with febuxostat at Fujita Health University Hospital from January 2012 to December 2013. The treatment goal was defined as achievement of serum urate levels of 6.0 mg/dL or lower within 16 weeks; this was the primary endpoint in the present study. Adverse events of febuxostat were defined as more than twofold increases in Common Terminology Criteria for adverse events scores from baseline. Results: We evaluated 82 patients treated with febuxostat during the observation period and classified them into male (n=53) and female (n=29) groups. The mean time to achievement of the treatment goal was significantly shorter in the female group (53 days) than in the male group (71 days). There were no significant differences in adverse events between the 2 groups.Conclusion: Our findings suggest that the efficacy of febuxostat in elderly female patients is superior to that in elderly male patients and that the safety is equivalent. Keywords: febuxostat, elderly female patients, hyperuricemia

Yosuke Togashi,1 Hidetoshi Hayashi,1–3 Kazuhiko Nakagawa,2 Kazuto Nishio1 1Department of Genome Biology, 2Department of Medical Oncology, Kindai University Faculty of Medicine, 3Department of Medical Oncology, Kishiwada Municipal Hospital, Osaka, Japan Abstract: Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood–brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted. Keywords: non-small-cell lung cancer, epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, EGFR mutation

Masao Saotome,1 György Hajnóczky,2 Hideki Katoh,1 Hiroshi Satoh,1 Hideharu Hayashi11Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USAAbstract: Coronary heart disease is a major cause of morbidity and mortality in advanced countries. Despite remarkable developments and achievements in the field of coronary intervention, such as percutaneous catheter intervention and coronary bypass surgery, the mortality from coronary heart disease remains high because of lack of effective cardioprotective therapy against ischemia/reperfusion injury after coronary recanalization. The mitochondria play a crucial role in determination of cell death in ischemia/reperfusion injury, and furthermore provide myocardial protection against ischemia/reperfusion injury by ischemic preconditioning. Functional and structural alterations in the mitochondria help to decide cell death and survival, and many investigations have been conducted to explore the pathophysiological mechanisms of “mitochondrial remodeling” to gain clues regarding ischemia/reperfusion injury. In this review, we summarize the current state of knowledge concerning the pathophysiological role of bidirectional (detrimental and defensive) “mitochondrial remodeling” via which cell death or survival is determined in coronary heart disease. Further, we discuss clinical trials of mitochondria-targeted treatment in patients with coronary heart disease.Keywords: coronary heart disease, mitochondrial remodeling, mitochondrial dynamics

Siddhartha Shankar Das, Hiroto Hayashi, Taiki Sato, Ren Yamada, Masahiro Hiratsuka, Noriyasu Hirasawa Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan Objective: Type 1 and 2 diabetes are characterized by elevated blood glucose levels and increased dipeptidyl peptidase 4 (DPP4) activity levels in the serum. However, previous studies reported a negative correlation between glucose concentrations and DPP4 levels. The purpose of this study was to elucidate the connection between glucose and DPP4 in adipocytes under physiological and diabetic conditions, because DPP4 is an adipokine. Methods: Blood glucose and serum DPP4 levels were measured, and adipocytes were collected from mice under normal, high-fat diet fed, and diabetic conditions. The adipocytes obtained were incubated for 24 hours in medium containing 5.5 or 25 mM glucose, and 3T3-L1 preadipocytes were differentiated under 5.5 or 25 mM glucose. Adipocytes from mice and 3T3-L1 were stimulated by tumor necrosis factor-α (TNF-α) for 24 hours. The levels of released and intracellular DPP4 were determined by enzyme-linked immunosorbent assay. Results: Mice fed high-fat diet had lower serum DPP4 levels in the first and second week than controls. However, this difference gradually disappeared over 6 weeks. The differentiation of 3T3-L1 adipocytes under 25 mM glucose produced lower DPP4 levels than those differentiated under 5.5 mM; this was also observed in isolated adipocytes from mice. However, these effects of glucose were lost in adipocytes from diabetic mice, and an increase in total DPP4 levels was observed. The stimulation of adipocytes with TNF-α increased the release of DPP4 irrespective of glucose concentration. Conclusion: The production of DPP4 in adipocytes was negatively regulated by 25 mM glucose under physiological conditions, but not in diabetic mice. Our results suggest that the observed increase in serum DPP4 levels may be attributed to increased production of DPP4 in adipocytes and an enhancement in TNF-α-induced release. Keywords: DPP4, 3T3-L1, diabetes, TNF-α

Eiji Kose,1 Taesong An,2 Akihiko Kikkawa,2 Yoshiaki Matsumoto,3 Hiroyuki Hayashi1 1Department of Pharmacotherapy, School of Pharmacy, Nihon University, Funabashi, 2Yokosuka Kyousai Hospital, Yokosuka, 3Department of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Funabashi, Japan Background: Chronic kidney disease (CKD) is associated with a high risk of cardiovascular disease complications. Therefore, medical institutions conduct educational hospitalization for early treatment and education of CKD patients. However, patients who have been discharged after achieving educational targets can end up showing poor symptoms at home. There also have been several cases of rehospitalization or disease aggravation. In this study, we analyzed rehospitalized patients who were discharged from the hospital after CKD educational hospitalization and investigated the purpose of analyzing rehospitalization factors. Materials and methods: This was an observational case-control study conducted at Yokosuka Kyousai Hospital. We performed univariate analysis using patient background features and laboratory data between a rehospitalization group and a no-rehospitalization group. Next, we performed multiple logistic regression analysis using the results of the univariate analysis. Results: From the results of this study, we identified independent risk factors, such as serum albumin level, heart-failure complications, and estimated glomerular filtration rate (eGFR). Moreover, the serum Alb level was identified as the most important risk factor for rehospitalization. Therefore, we considered that it is important to live a life that makes it possible to maintain CKD stage G3b for a long time after discharge, because the cutoff level of eGFR is 31 mL/minute/1.73 m2. Conclusion: We believe that it is important to educate patients, their families, and medical staff on the importance of early detection and treatment, and we consider that this approach is important to inclusively protect the kidney. Keywords: albumin, glomerular filtration rate, cardiovascular disease, stages of chronic kidney disease

Tomohiro Mizuno,1,2,* Takahiro Hayashi,3,* Rina Kato,1 Ayaka Noguchi,1 Hiroki Hayashi,2 Yukio Yuzawa,2 Shigeki Yamada,3 Tadashi Nagamatsu1 1Department of Analytical Pharmacology, Meijo University Faculty of Pharmacy, Nagoya; 2Department of Nephrology, 3Department of Clinical Pharmacy, School of Medicine, Fujita Health University, Toyoake, Japan *These authors contributed equally to this work Background: Patients with end-stage renal disease (ESRD) have symptoms related to severe anemia, edema, and heart failure. Although dialysis improves ESRD syndromes, the optimum timing for initiation of dialysis is unclear. Recent observational studies have suggested that early commencement of dialysis can be harmful. Given that early dialysis may increase the risk of death, avoiding an early start to dialysis is recommended. Patients with diabetic nephropathy (DN) may have risk factors for early dialysis. However, the risk factors for early dialysis are unclear in ESRD patients with DN. The aim of this study was to elucidate the risk factors for early initiation of dialysis in patients with DN and ESRD. Methods: From April 2009 to December 2012, we identified Japanese DN patients with an estimated glomerular filtration rate of less than 15 mL/minute/1.73 m2. The patients were divided into late or early dialysis groups based on the timing of start of dialysis. Results: We evaluated 52 patients who commenced dialysis during the observation period, including 33 in the late dialysis group and 19 in the early dialysis group. There was a significant association between early dialysis and age ≥65 years (odds ratio 4.59). The incidence of pneumonia before starting dialysis was significantly higher in elderly patients than in nonelderly patients. Conclusion: Our findings suggest that elderly patients with DN and ESRD have an increased risk of early initiation of dialysis, and occurrence of pneumonia is also associated with early dialysis. To avoid early commencement of dialysis, booster pneumococcal vaccination could be useful in elderly DN patients with ESRD. Keywords: early dialysis, diabetes mellitus, nephropathy, elderly patients, estimated glomerular filtration rate

Jinichi Hirano,1,2 Koichiro Watanabe,3 Takefumi Suzuki,1,4 Hiroyuki Uchida,1 Ryosuke Den,5 Taishiro Kishimoto,1 Takashi Nagasawa,5 Yusuke Tomita,4 Koichiro Hara,6 Hiromi Ochi,7 Yoshimi Kobayashi,1 Mutsuko Ishii,1 Akane Fujita,1 Yoshihiko Kanai,1 Megumi Goto,1 Hiromi Hayashi,1 Kanako Inamura,1 Fumiko Ooshima,1 Mariko Sumida,1 Tomoko Ozawa,1 Kayoko Sekigawa,1 Maki Nagaoka,1 Kae Yoshimura,1 Mika Konishi,1 Ataru Inagaki,1 Takuya Saito,8 Nobutaka Motohashi,9 Masaru Mimura,1 Yoshiro Okubo,8 Motoichiro Kato,11Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; 2Ohizumi Hospital, Tokyo, Japan; 3Department of Psychiatry School of Medicine, Kyorin University, Tokyo, Japan; 4Inokashira Hospital, Tokyo, Japan; 5Komagino Hospital, Tokyo, Japan; 6Asai Hospital, Chiba, Japan; 7Kurumegaoka Hospital, Tokyo, Japan; 8Department of Psychiatry School of Medicine, Nippon Medical School, Tokyo, Japan; 9Department of Psychiatry, School of Medicine, University of Yamanashi, Yamanashi, JapanObjective: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce.Methods: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists.Results: Forty-two patients (21 females, 39.0 ± 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group.Conclusion: While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.Keywords: algorithm, open-label clinical trial, measurement-based treatment, schizophrenia, treatment-as-usual

Tsuneaki Kenzaka,1 Masanobu Okayama,2 Shigehiro Kuroki,1 Miho Fukui,3 Shinsuke Yahata,3 Hiroki Hayashi,3 Akihito Kitao,3 Eiji Kajii,2 Masayoshi Hashimoto41Division of General Medicine, 2Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke; 3Department of General Medicine, Toyooka Public Hospital, Toyooka; 4Department of Family and Community Medicine, Kobe University Graduate School of Medicine, Kobe, JapanBackground: The aim of this study was to evaluate the clinical usefulness of a semiquantitative procalcitonin kit for assessing severity of sepsis and early determination of mortality in affected patients.Methods: This was a prospective, observational study including 206 septic patients enrolled between June 2008 and August 2009. Disseminated intravascular coagulation (DIC), Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II scores were measured, along with semiquantitative procalcitonin concentrations. Patients were divided into three groups based on their semiquantitative procalcitonin concentrations (group A,